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Sex Differences in Molecular Rhythms in the Human Cortex

  • Author Footnotes
    1 RWL and XX contributed equally to this work.
    Ryan W. Logan
    Footnotes
    1 RWL and XX contributed equally to this work.
    Affiliations
    Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts

    Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine
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  • Author Footnotes
    1 RWL and XX contributed equally to this work.
    Xiangning Xue
    Footnotes
    1 RWL and XX contributed equally to this work.
    Affiliations
    Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Kyle D. Ketchesin
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
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  • Gabriel Hoffman
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York

    Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York
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  • Panos Roussos
    Affiliations
    Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York

    Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York

    Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York

    Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York

    Mental Illness Research, Education, and Clinical Center, James J. Peters VA Medical Center, Bronx, New York
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  • George Tseng
    Affiliations
    Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Colleen A. McClung
    Affiliations
    Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine

    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
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  • Marianne L. Seney
    Correspondence
    Address correspondence to Marianne L. Seney, Ph.D.
    Affiliations
    Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania

    Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania
    Search for articles by this author
  • Author Footnotes
    1 RWL and XX contributed equally to this work.

      Abstract

      Background

      Diurnal rhythms in gene expression have been detected in the human brain. Previous studies found that males and females exhibit 24-hour rhythms in known circadian genes, with earlier peak expression in females. Whether there are sex differences in large-scale transcriptional rhythms in the cortex that align with observed sex differences in physiological and behavioral rhythms is currently unknown.

      Methods

      Diurnal rhythmicity of gene expression was determined for males and females using RNA sequencing data from human postmortem dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Sex differences among rhythmic genes were determined using significance cutoffs, threshold-free analyses, and R2 difference. Phase concordance was assessed across the DLPFC and ACC for males and females. Pathway and transcription factor analyses were also conducted on significantly rhythmic genes.

      Results

      Canonical circadian genes had diurnal rhythms in both sexes with similar amplitude and phase. When analyses were expanded to the entire transcriptome, significant sex differences in transcriptional rhythms emerged. There were nearly twice as many rhythmic transcripts in the DLPFC in males and nearly 4 times as many rhythmic transcripts in the ACC in females. Results suggest a diurnal rhythm in synaptic transmission specific to the ACC in females (e.g., GABAergic [gamma-aminobutyric acidergic] and cholinergic neurotransmission). For males, there was phase concordance between the DLPFC and ACC, while phase asynchrony was found in females.

      Conclusions

      There are robust sex differences in molecular rhythms of genes in the DLPFC and ACC, providing potential mechanistic insights into how neurotransmission and synaptic function are modulated in a circadian-dependent and sex-specific manner.

      Keywords

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